Smoothies are an excellent way to intake nutrients and bioactive compounds from both the fruits and the milk or soymilk with which they are made. High pressure processing (HPP) is an efficient alternative to traditional thermal pasteurization (TP), obtaining microbiologically-safe smoothies with minimum impact on nutritional and sensorial properties. Untreated, pasteurized (80 °C/3 min) and HPP (450–650 MPa for 3 min at 20 °C) milk- and soy-smoothies were compared. Milk- and soy-smoothies showed a total reduction in microorganisms after pasteurization and HPP at the pressure conditions applied. HPP maintained microbial stability until the end of the storage period (45 days at 4 °C). Soluble sugars (glucose and fructose), organic acids (citric, malic, tartaric, oxalic and quinic) and minerals (sodium, potassium, calcium, magnesium, iron, copper, zinc and manganese) showed no significant changes after the treatments and storage. No significant differences were found in sensorial attributes between untreated and HPP samples, although the aroma and acceptability scores decreased significantly for pasteurized smoothies. Based on the data obtained, 450 MPa are sufficient to obtain safe smoothies whose organoleptic properties are equally acceptable to consumers as freshly-made smoothies.